(R)-α-methyl-N-[3-[3-(trifluoromethyl)phenyl]propyl]-1-naphthalenemethane amine (herein “Cinacalcet” or “CNC”) has a CAS number of 226256-56-0, a formula of C22H22F3N, and the following structure.

Cinacalet is the free base form of cinacalcet hydrochloride (herein “CNC-HCl”), having a CAS number of 364782-34-3 and the following structure:

CNC-HCl is marketed as SENSIPAR™, and was the first drug in a class of compounds known as calcimimetics to be approved by the FDA. Calcimimetics are a class of orally active, small molecules that decrease the secretion of parathyroid hormone (“PTH”) by activating calcium receptors. The secretion of PTH is normally regulated by the calcium-sensing receptor. Calcimimetic agents increase the sensitivity of this receptor to calcium, which inhibits the release of parathyroid hormone, and lowers parathyroid hormone levels within a few hours. Calcimimetics are used to treat hyperparathyroidism, a condition characterized by the over-secretion of PTH that results when calcium receptors on parathyroid glands fail to respond properly to calcium in the bloodstream. Elevated levels of PTH, an indicator of secondary hyperparathyroidism, are associated with altered metabolism of calcium and phosphorus, bone pain, fractures, and an increased risk for cardiovascular death. As a calcimimetic, CNC-HCl is approved for treatment of secondary hyperparathyroidism in patients with chronic kidney disease on dialysis. Treatment with CNC-HCl lowers serum levels of PTH as well as the calcium/phosphorus ion product, a measure of the amount of calcium and phosphorus in the blood.
Inorganic ion receptor active molecules, especially calcium receptor-active molecules, such as those having the general structure of cinacalcet, are disclosed in U.S. Pat. No. 6,011,068. U.S. Pat. No. 6,211,244 discloses calcium receptor-active compounds related to cinacalcet and methods of making such compounds. Cinacalcet and its enantiomer may be produced by various methods, using the processes disclosed in U.S. Pat. No. 6,211,244; DRUGS OF THE FUTURE, 27 (9), 831 (2002); U.S. Pat. Nos. 5,648,541; 4,966,988; and Tetrahedron Letters (2004) 45: 8355, footnote 12.
Like any synthetic compound, cinacalcet salt can contain process impurities, including unreacted starting materials, chemical derivatives of impurities contained in starting materials, synthetic by-products, and degradation products. It is also known in the art that impurities present in an active pharmaceutical ingredient (“API”) may arise from degradation of the API, for example, during storage or during the manufacturing process, including the chemical synthesis.
In addition to stability, which is a factor in the shelf life of the API, the purity of the API produced in the commercial manufacturing process is a necessary condition for commercialization. Impurities introduced during commercial manufacturing processes must be limited to very small amounts, and are preferably substantially absent. For example, the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (“ICH”) Q7A guidance for API manufacturers requires that process impurities be maintained below set limits. The guidance specifies the quality of raw materials, and process parameters, such as temperature, pressure, time, and stoichiometric ratios, including purification steps, such as crystallization, distillation, and liquid-liquid extraction, in the manufacturing process.
The product mixture of a chemical reaction is rarely a single compound with sufficient purity to comply with pharmaceutical standards. Side products and by-products of the reaction and adjunct reagents used in the reaction will, in most cases, also be present in the product mixture. At certain stages during processing of an API, such as cinacalcet salt, it must be analyzed for purity, typically by high performance liquid chromatography (“HPLC”) or thin layer chromatography (“TLC”), to determine if it is suitable for continued processing and, ultimately, for use in a pharmaceutical product. The API need not be absolutely pure, as absolute purity is a theoretical ideal that is typically unattainable. Rather, purity standards are set with the intention of ensuring that an API is as free of impurities as possible, and, thus, are as safe as possible for clinical use. In the United States, the Food and Drug Administration guidelines recommend that the amounts of some impurities be limited to less than 0.1 percent.
Generally, side products, by-products, and adjunct reagents (collectively “impurities”) are identified spectroscopically and/or with another physical method, and then associated with a peak position, such as that in a chromatogram or a spot on a TLC plate. See Strobel, H. A.; Heineman, W. R., Chemical Instrumentation: A Systematic Approach, 3rd ed. (Wiley & Sons: New York 1989), p. 953 (“Strobel”). Thereafter, the impurity can be identified, e.g., by its relative position in the chromatogram, where the position in a chromatogram is conventionally measured in minutes between injection of the sample on the column and elution of the particular component through the detector. The relative position in the chromatogram is known as the “retention time.”
The retention time can vary about a mean value based upon the condition of the instrumentation, as well as many other factors. To mitigate the effects such variations have upon accurate identification of an impurity, practitioners use the relative retention time (“RRT”) to identify impurities. See Strobel p. 922. The RRT of an impurity is its retention time divided by the retention time of a reference marker. It may be advantageous to select a compound other than the API that is added to, or present in, the mixture in an amount sufficiently large to be detectable and sufficiently low as not to saturate the column, and to use that compound as the reference marker for determination of the RRT.
Those skilled in the art of drug manufacturing, research and development understand that a compound in a relatively pure state can be used as a “reference standard.” A reference standard is similar to a reference marker, but can be used for quantitative analysis, rather than simply qualitative analysis, as with a reference standard. A reference standard is an “external standard,” when a solution of a known concentration of the reference standard and an unknown mixture are analyzed using the same technique. See Strobel p. 924; Snyder, L. R.; Kirkland, J. J. Introduction to Modern Liquid Chromatography, 2d ed. (John Wiley & Sons: New York 1979), p. 549 (“Snyder”). The amount of the compound in the mixture can be determined by comparing the magnitude of the detector response. See U.S. Pat. No. 6,333,198, incorporated herein by reference.
The reference standard can also be used to quantify the amount of another compound in the mixture if a “response factor,” which compensates for differences in the sensitivity of the detector to the two compounds, has been predetermined. See Strobel p. 894. For this purpose, the reference standard is added directly to the mixture, and is known as an “internal standard.” See Strobel p. 925; Snyder p. 552.
The reference standard can serve as an internal standard when, without the deliberate addition of the reference standard, an unknown mixture contains a detectable amount of the reference standard compound using the technique known as “standard addition.”
In the “standard addition technique”, at least two samples are prepared by adding known and differing amounts of the internal standard. See Strobel, pp. 391-393; Snyder pp. 571, 572. The proportion of the detector response due to the reference standard present in the mixture without the addition can be determined by plotting the detector response against the amount of the reference standard added to each of the samples, and extrapolating the plot to zero concentration of the reference standard. See, e.g., Strobel, FIG. 11.4, p. 392. The response of a detector in HPLC (e.g. ultraviolet (“UV”) detectors or refractive index detectors) can be and typically is different for each compound eluting from the HPLC column. Response factors, as known, account for this difference in the response signal of the detector to different compounds eluting from the column.
As is known by those skilled in the art, the management of process impurities is greatly enhanced by understanding their chemical structures and synthetic pathways, and by identifying the parameters that influence the amount of impurities in the final product.
Impurities in cinacalcet including, but not limited to, unreacted starting materials, by-products of the reaction, products of side reactions, or degradation products are undesirable and, in extreme cases, might even be harmful to a patient being treated with a dosage form containing the API. Thus, there is a need in the art for a method for determining the level of impurities in cinacalcet samples and removing the impurities.